The objective of the proposed study is to evaluate the role of Thromboxane A2 (TxA2) and prostaglandins as pathogenesis factors in shock. Recent studies from our laboratory have demonstrated that essential fatty acid (EFA)-deficient rats are remarkably tolerant to bacterial endotoxin. These studies were initiated to test the hypothesis that the depletion of the thromboxane precursor, arachidonic acid, that occurs in EFA-deficiency results in decreased mortality from endotoxemia. Because the role of prostaglandins in shock is controversial and the potential role of the proaggregatory-vasoconstrictor, TxA2, has not been evaluated, we will assess plasma levels of TxB2, (a stable metabolite of TxA2), PGE2 and 6-keto-PGF1 alpha, (a stable metabolite of prostacyclin) in control and EFA-deficient rats during endotoxemia. Additionally, the effect of administration of arachidonic and dihomo-gamma-linolenic acid in EFA-deficient rats on TxB2 and prostaglandin formation and susceptibility to endotoxic shock will be assessed. Since our preliminary observations denote that the Tx synthetase inhibitor, imidazole, and a TxA2 antagonist, 13-Azaprostanoic acid, protect normal non-deficient rats from endotoxic shock, we will further assess the efficacy of specific inhibitors and antagonists of TxA2 in preventing lethal endotoxemia and its associated microcirculatory failure. Such studies will be paralleled by an evaluation of endotoxin induced altered hemodynamics and blood coagulative disorders in normal, EFA-deficient and appropriately treated groups of rats. The long term goals are to delineate potential organ and cellular sites of Tx release in shock and to develop potential new therapeutic agents. Such studies will be expanded to other shock models including E. coli septic shock, traumatic, splanchnic arterial occlusion shock, and hemorrhagic shock. Our proposal, therefore, will attempt to elucidate the role of TxA2 and prostaglandins in the pathogenesis of shock.